Submissions for variant NM_000136.3(FANCC):c.416G>A (p.Gly139Glu) (rs1800362)

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000120977	SCV000168401	benign	not specified	2013-10-31	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV000205371	SCV000261883	benign	Fanconi anemia	2020-12-06	criteria provided, single submitter	clinical testing
PreventionGenetics,PreventionGenetics	RCV000120977	SCV000302520	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV001095332	SCV000481135	likely benign	Fanconi anemia, complementation group C	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics	RCV000432064	SCV000511767	likely benign	not provided	2016-09-20	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
Ambry Genetics	RCV000575908	SCV000673292	benign	Hereditary cancer-predisposing syndrome	2016-08-18	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000432064	SCV000695429	benign	not provided	2016-04-29	criteria provided, single submitter	clinical testing	Variant summary: The c.416G>A variant affects a conserved nucleotide, resulting in amino acid change from Gly to Glu. 4/4 in-silico tools predict damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is found in 508/120796 control chromosomes (6 homozygotes) at a frequency of 0.0042054. The variant was present predominantly in the African population at a frequency of 4.5% which is about 26 times of the maximal expected frequency of a pathogenic allele (0.0017678), strongli indicating this variant is benign. In addition, publications/clinical laboratories have classified this variant as benign. Taken together, this variant was classified as benign.
Mendelics	RCV000988218	SCV001137855	benign	Fanconi anemia, complementation group A	2019-05-28	criteria provided, single submitter	clinical testing
ITMI	RCV000120977	SCV000085145	not provided	not specified	2013-09-19	no assertion provided	reference population
Leiden Open Variation Database	RCV000432064	SCV001365293	uncertain significance	not provided	2020-02-28	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach.
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV001355214	SCV001550033	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The FANCC p.Gly139Glu variant was identified in 5 of 1190 proband chromosomes (frequency: 0.0042) from individuals or families with Fanconi anemia and pancreatic cancer, and was present in 1 of 1362 control chromosomes (frequency: 0.00073) from healthy individuals (Couch_2005_15695377, Verlander_1994_8128956). The variant was also identified in dbSNP (ID: rs1800362) as “With other allele,” ClinVar (as benign by GeneDx, Invitae, PreventionGenetics, Ambry Genetics, and Laboratory Corporation of America, and as likely benign by Illumina and Center for Pediatric Genomic Medicine Children's Mercy Hospital), and Clinvitae (as in ClinVar) databases. The variant was not identified in Cosmic, MutDB, or LOVD 3.0 databases. The variant was identified in control databases in 1253 of 276924 chromosomes (30 homozygous) at a frequency of 0.004525 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1133 of 24008 chromosomes (freq: 0.04719), Other in 13 of 6454 chromosomes (freq: 0.002014), Latino in 82 of 34404 chromosomes (freq: 0.002383), European (Non-Finnish) in 14 of 126516 chromosomes (freq: 0.000111), and South Asian in 11 of 30768 chromosomes (freq: 0.000358), while the variant was not observed in the Ashkenazi Jewish, East Asian, or European Finnis populations. The p.Gly139Glu residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.